Diffuse large B-cell lymphoma (DLBCL) is a common cancer in the US, causing tens of thousands of deaths each year and its incidence is on the rise. MicroRNAs (miRNAs) are small non-coding RNAs that are often mis- regulated in lymphoma and leukemia. In particular, miR-155 is up-regulated in multiple lymphoma/leukemia sub- types (notably DLBCL). Plus, direct evidence exists to show that its over-expression causes DLBCL in human DLBCL xenografts and transgenic mouse models. Interestingly, the tumors induced by over-expression of miR- 155 depend on the continued expression of the miRNA for survival, since if the miRNA is withdrawn, the tumors rapidly regress via apoptosis. This property of ?oncogene addiction? makes this class of miRNAs ideal targets for future anti-cancer therapy and promoted the initiation of a clinical trial to inhibit oncomiR-155 via intratumoral delivery of Cobomarsen in Cutaneous T-cell Lymphoma (CTCL) and DLBCL. While remarkable progress has been made in the past few years with FDA approvals of antisense and RNAi drugs, therapeutic miRNA targeting still lags behind, largely due to issues related to selective delivery and toxicity. Here we propose to exploit the striking nature of oncogene addiction to develop potential therapeutics tailored to antagonize this crucial oncomiR in a safe and effective manner. We previously published an approach to target anti-miR-155 peptide nucleic acids (PNAs) to the acidic tumor microenvironment using pHLIP (pH Low Insertion Peptide), with significant effects in a mouse model of lymphoma. pHLIP is a 36-amino acid peptide that adopts an ?-helical conformational change at low pH (< pH 6.5) that facilitates insertion of its C-terminus across lipid bilayers in the acidic tumor microenvironment. Here we propose a multi-disciplinary project focused on translating next-generation PNA and pHLIP technology to allow highly-specific targeting and improved efficacy targeting oncogenic miR-155 in acidic tissues in miR-155-addicted cancers, with a favorable therapeutic window. Unlike most nucleic acids, PNAs are a synthetic DNA mimics in which the phosphodiester backbone is substituted with a neutral N-(2-aminoethyl) glycine backbone. PNAs can bind single-strand targets with high specificity and affinity and are not susceptible to proteases or nucleases, making PNAs ideal molecules for targeting miRNAs. To further improve the effectiveness of antimiR PNAs, we will exploit a new class of PNA analogs, designated gamma PNAs (gPNAs) that are conformationally pre-organized and so have advantageous binding as well as solubility properties that should increase their effectiveness as antimiR agents. As proof of principle for our stable next generation pHLIP-conjugated, chemically modified gamma PNAs (gPNAs) as cancer therapeutics, we propose to test delivery and efficacy in lymphoma cancer models in this project (cell lines, xenografts, PDX and GEMMs), with the ultimate goal of preparing a drug suitable for clinical trials. Investigation of these methods to exploit miRNA addiction with novel oligomers targeted to the acidic microenvironment will inform the development of molecularly targeted cancer therapeutics for lymphoma/leukemia and other tumors.